Our research interest is focused on the role of microglia at the late stage and early stage of Alzheimer’s disease (AD). At the late stage, overactivated microglia clustering at neuritic plaques constantly release neurotoxins, which actively contribute to progressive neurodegeneration in AD. Therefore, attenuating microglia clustering can reduce the focal neuroinflammation at neuritic plaques. We have identified CCL5 and CCL2 as prominent chemokines mediating the chemotactic migration of microglia toward Abeta aggregates. We find that TGF-beta1 reduces Abeta-induced microglial chemotaxis through the SMAD2 pathway. The down-regulation of CCL5 by TGF-beta1, at least, partially contributes to the clustering of microglia at Abeta aggregates. TGF-beta1 may ameliorate microglia-mediated neuroinflammation in AD by preventing activated microglia clustering at neuritic plaques.

At the early stage, the accumulation of soluble oligomeric amyloid-beta peptide prior to the presence of senile plaques contributes to synaptic and memory deficits in AD. Although microglia are prominent on oAbeta uptake in CNS, the mechanism of mediating microglial oAbeta clearance remains unclear. Our study suggests that scavenger receptor at the plasma membrane and lysosomal capthesin B are critical for microglial oAbeta clearance. This study provides the first insight into how microglia are involved in the clearance of oAbeta and their roles at the early stages of AD.

More than 95% of AD are sporadic without familial history. During the aging process, vesicular damages are associated with sporadic AD. Our recent project is focused on establishing stroke animal models and ask the impact of vesicular damages on the initiation of AD .